I've been putting some energy into cleaning up my in-box over the past six months, and have finally made some serious progress.  (And no, I don't use Gmail.  Judging from what others say, it sounds seriously unreliable.)  I've read a slew of posts and articles on this topic - I'm guessing we've all seen a few articles on this (e.g., "Managing Your Mailbox Tutorial"; "4 Ways to Take Control of Your E-mail Inbox"; "Inbox Zero: Action Based Email").  I didn't find any of these articles particularly helpful.  What I found most valuable wasn't a sorting system, or rules, or buckets, or anything like that.  In fact, for me the key wasn't to focus on my in-box at all.  I achieved a manageable in-box through implementing a simple rule for sent items: 

don't save sent items as a default, and every time you send an email, double check to see whether it's important enough to save, and if so, route it to the appropriate folder before sending it.

This sounds irrelevant to organizing your in-box, but I found that it got me to in-box zero more effectively than any of the systems I came across.  After implementing this rule, I typically operate with approximately 25-35 emails in my in-box and zero in my sent folder.  The stuff in my in-box is stuff from the last 30 days and every so often I'll go through and archive stuff that's more than 30 days old.  Implementing this simple rule highlighted the fact that I save way too many emails.  Part of that is a function of the fact that I'm a lawyer and I'm fairly conservative about keeping records.  But when I thought about it, I realized that I really didn't need to save many of the menial emails I send out, like the ones that say "coffee at 4 sounds good," or "thanks for taking care of this".  For some odd reason, with my sent items always at zero my in-box became much easier to tackle.  There's no rational explanation for it, but it is what it is.  It works!

Everyone's different, and there's obviously no one size fits all approach, but this works for me.